Journal
JOURNAL OF MOLECULAR CELL BIOLOGY
Volume 2, Issue 6, Pages 345-356Publisher
OXFORD UNIV PRESS
DOI: 10.1093/jmcb/mjq032
Keywords
hypoxia; T-cell intracellular antigen-1; TIA-1-related protein; hypoxia-inducible factor-1
Categories
Funding
- University Medical Center Giessen and Marburg (UKGM)
- Excellence Cluster Cardiopulmonary System (ECCPS)
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T-cell intracellular antigen (TIA)-1 and TIA-1-related protein (TIAR) are mRNA-binding proteins that can aggregate within granules under specific stress conditions. In this study, we analyzed TIAR/TIA-1 aggregation under different hypoxic conditions, and studied the effects on the hypoxia-inducible factor (HIF)-1 alpha in different cancer cell lines. Under acute and pronounced hypoxic conditions TIAR/TIA-1 co-aggregated to granules and positive co-staining with eIF3 eta marker suggested these to represent stress granules. In parallel, HIF-1 alpha expression was blocked in cells displaying TIAR/TIA-1 granules. Silencing of TIAR and TIA-1 caused upregulation of HIF-1 alpha expression, as demonstrated by western blot, immunocytochemistry and HIF-1-dependent reporter gene expression. Additionally, a critical region of the 3' end of the untranslated HIF-1 alpha mRNA with possible adenosine-uridine-rich elements (AREs) was coupled to the luciferase reporter gene, causing downregulation of expression. Employing this reporter construct, inhibition of TIAR by siRNA attenuated the inhibitory cis-effect of this ARE-sequence. Furthermore, immunohistochemical analysis of A549 cell tumor xenografts revealed a nearly complementary expression of HIF-1 alpha and TIAR reflecting the control of HIF-1 alpha expression by TIAR as revealed in the cell culture studies. In sum, rapid and severe hypoxia caused co-aggregation of TIAR/ TIA-1 and these proteins suppressed HIF-1 alpha expression.
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